The 2 hydrazine derivatives isoniazid (INH) and procarbazine hydrochloride (P) were injected intravenously into rabbits. Radioactive thymidine was injected into both testicles. Rabbits were ejaculated repeatedly, sperms were counted and incorporation of [3H] thymidine into sperm head DNA was determined by liquid scintillation counting. In P-treated rabbits (5 and 50 mg/kg) radioactivity was significantly increased in sperms that were in late phases of spermatocyte and early phases of spermatid maturation at the time of treatment. This indicates that DNA repair synthesis, (unscheduled DNA synthesis, UDS) occurred following drug-induced DNA damage in these germ cells. Normal DNA synthesis in spermatogonia was inhibited by the high dose only. INH (50 and 125 mg/kg) did not cause UDS in spermatocytes and spermatids and did not affect normal DNA synthesis in spermatogonia. The results are in agreement with literature data indicating that P is a potent mutagen and carcinogen. INH, on the other hand, has weak mutagenic and carcinogenic activities that are most apparent in mice.

Animals↗

PubMedDate not supplied

Response force titration for the assessment of the neuromuscular toxicity of 2,5-hexanedione in rats.

A silent, non-moving glass lever combined with strain gauges and mounted in an operant chamber measured the vertical isometric force exerted by the forepaw of rats. Every weekday the rats were subjected to a force titration schedule consisting of a sequence of discrete trials signalled by a lever light. The required force, above which a water reinforcement is delivered, was regulated by a generalized bisection algorithm. A stable force level which the rat was able to attain at 50% of the trials was quickly reached in each session by this algorithm. This technique was used to measure the neuromuscular performance decrement due to repeated 2,5-hexanedione treatment (250 and 500 mg/kg/day per os). The results were compared with fore- and hindlimb grip strength measurements on the same animals. This experiment showed that the force titration technique is able to distinguish between motivational and true force decrements, a distinction which cannot be made by the grip strength technique.

Analysis of Variance↗

PubMedDate not supplied

Biochemical mechanisms of quinidine cardiotoxicity.

"Quinidine-like action" and the synonym "membrane-stabilizing activity" are often encountered descriptions for adverse cardiac effects of drugs. Quinidine, 50 mg/kg/day, 5 days/week for 4 weeks, was found to cause disturbance of intracardiac conduction in rats. It was the purpose of this study to investigate the effect of the same dose of quinidine on biochemical activities involved in the energy metabolism of the heart. Electron transfer activities in heart mitochondria were progressively slowed down. At the same time, uncoupling of oxidative phosphorylation was observed and mitochondrial creatinephosphate kinase activity decreased. Concomitantly, mitochondria showed a progressive loss in semipermeability, manifested by an increasing creatine content. Total adenine nucleotides (especially ATP) content declined to 65% of control values to return to normal levels at the end of the 4 week treatment period. Calcium-binding activity and various ATPases (Na/K, Mg, Ca) of myocyte membranes (sarcolemma + sarcoplasmatic reticulum fraction) were also impaired by quinidine. Protein synthesis in total heart tissue and heart mitochondria, an energy-requiring process, was also moderately inhibited by quinidine. Maximal quinidine concentration in heart tissue was 0.123 microgram/g fresh weight 24 h after the last of 19 medications.

Adenine Nucleotides↗

PubMedDate not supplied

The significance of pharmacologic screening tests in the preclinical safety evaluation of new drugs.

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Animals↗

PubMedDate not supplied

Pharmacology of vitamin A acid (beta-all transretinoic acid).

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Alkaline Phosphatase↗

PubMedDate not supplied

Toxicologic screening of daunorubicin (NSC-82151), adriamycin (NSC-123127), and their derivatives in rats.

The cardiotoxicity of seven anthracycline antibiotics was evaluated in small groups of rats treated with repeated intraperitoneal injections. The electrocardiogram showed a widening of the QRS complex often with the appearance of a distinct S-wave trough and occasionally with an increase or flattening of the T wave. Ventricular extrasystoles, intraventricular block, bradycardia, and heart failure developed either during treatment or after discontinuation of therapy. Based on the cumulative dose required to induce significant electrocardiographic changes, the compounds were ranked in the following order of decreasing cardiotoxicity: adriamycin, daunorubicin, NSC-149584, rubidazone, NSC-143496, daunomycin-semicarbazone, and NSC-118714. For three of these compounds used in humans (adriamycin, daunorubicin, and rubidazone) the rat screening results are in good agreement with the clinically observed cardiotoxicity.

Animals↗